The ultimate aim of this proposal is to define the pathogenetic mechanisms underlying renal cyst formation using a unique transgenic mouse renal model of human autosomal polycystic kidney disease (ADPKD) developed in our laboratory. Insights into the molecular mechanisms which govern cystogenesis may have important implications for patients suffering from ADPKD or other types of renal cystic diseases. A major objective is to define and isolate the pkd1 gene. At present, little is known about the genetic defect(s) in ADPKD or its biological consequence at the protein level. We have recently produced a novel transgenic mouse model of ADPKD in which there is renal epithelial overexpression of the c-myc proto-oncogene. This unique model provides a powerful experimental system for studying molecular genetic analysis of PKD. A physiopathology study of these mice will determine if the characteristic features observed in human are reproduced in this mouse renal model in order to assess its eventual utility in the screening of therapeutic agents. A first approach will address the questions of the role of c-myc in PKD. To this effect, transgenic mice will be generated with novel transgene constructs in which the c-myc gene has been substituted for other proto-oncogenes or growth factors with similar properties. Analysis of gene expression and renal phenotype of these transgenic mice will provide information about the specificity of c-myc in this model and the etiology of PKD. Second, the regulatory elements directing expression to the renal epithelial tubular cell will be determined in transgenic mice. Third, a search for genes expressed in renal epithelial cells will be done, candidate genes isolated and regulator genes implicated in expression of renal epithelial tubular genes will be identified. We will screen a variety of spontaneous mouse mutants with renal cystic conditions for expression of these genes which could be implicated in cystogenesis. In this manner, we will define pathogenetic factors operant in ADPKD and which may also be common to other renal cystic conditions. In addition, we plan to identify the pkd1 gene by using transgenic mice as an in vivo assay system for PKD. This approach will have a dual biological significance for identification of pkd1 gene and bridging the animal model to the human disease.